Type 1 diabetes (T1D) is characterized by the CD4+ and CD8 + T cell mediated destruction of the insulin producing ( cells. We and others have demonstrated that antigen-specific based immunotherapies can be effective at suppressing early and late stages of preclinical T1D in nonobese diabetic (NOD) mice. However, little is known regarding the efficacy of antigen-specific immunotherapy once overt diabetes is established. This is an important issue for islet transplantation and the prevention of autoimmune mediated destruction of the graft in a diabetic recipient. Recently we found that administration of plasmid DNAs (pDNAs) encoding the beta cell autoantigen GAD65, IL-4 and IL-10 protected islet grafts from recurrent autoimmune destruction in diabetic NOD recipients. Furthermore, varying the conditions of pDNA vaccination resulted in different degrees of islet graft protection. Interestingly, the type and frequency of immunoregulatory T effectors induced via pDNA administration correlated with the efficacy of islet graft protection. The current application proposes to define the effector cells and mechanisms that immunoregulate ( cell autoimmunity at the clinical end stage of T1D, and mediate long-term islet graft survival. In this way, insight will be gained into the key events that influence autoimmune destruction of islet grafts, in addition to obtaining a better understanding of the parameters which may influence the efficacy of antigen-specific based immunotherapy in a clinical setting.